The microbiome in prematurity: Key messages from emerging science

Studies of the placental microbiome are a window into the complex interplay between microbiota and host in spontaneous PTB.

Although preterm birth (PTB) (<37 weeks at delivery) is a leading cause of perinatal morbidity and mortality worldwide, reliable tools to clinically predict both its occurrence and severity or the co-occurrence of infant morbidity are lacking. This clinical dilemma is further exacerbated by the absence of highly efficacious primary and secondary prevention measures, as well as reliable interventions.1,2 Perhaps the greatest obstacle to their discovery is the likely multifactorial and varied etiology of PTB, which is undoubtedly a reflection of the “lumping” of what is actually a syndrome with varied etiologies into a single disorder. Indeed, PTB can be readily separated into spontaneous and indicated PTB, and, thus, treatment or prevention for one might be counterproductive for the other.

Take for example any day on a labor and delivery ward around the United States: 2 women deliver at 32 and 2/7 weeks’ gestation. The first was induced for 2 days secondary to her diagnosis of severe preeclampsia with concern for worsening symptoms. The second woman presented 3 hours ago in active labor with advanced cervical dilatation to 7 cm and just ruptured her membranes. Working to identify the etiology of early severe preeclampsia in the first patient could be of benefit in future pregnancies (eg, treating underlying systemic lupus erythematosus, providing low-dose aspirin). Conversely, in our second patient, attempts at preventing recurrent spontaneous PTB will be of benefit (eg, via administration of 17-alpha hyrdoxyprogesterone caproate). However, both outcomes would be classified as PTB even though their etiologies are likely quite distinct. Given the heterogeneous nature of PTB, we will focus this review on the spontaneous PTB syndrome and the potential of underlying inflammatory and infectious causes of its occurrence.

Etiologies of spontaneous preterm birth

Observational studies have identified a number of environmental and host factors that carry a greater risk of spontaneous PTB, including a prior history, maternal smoking, and maternal race/ethnicity.3 Intrauterine infection and associated inflammation has also been hypothesized as a potential contributor to spontaneous PTB, but a specific infectious etiology has yet to be identified. Moreover, empirical administration of antimicrobials for presumptive infectious processes have been uniformly shown to be nonefficacious in preventing spontaneous PTB, and may instead increase risk.4 In addition, bacterial vaginosis (BV) increases risk of PTB, but while antibiotic treatment of symptomatic BV is efficacious, PTB rates are unaffected.5,6 Even more concerning, several studies have found that empiric antibiotic administration to asymptomatic women increased the rate of PTB.7,8 These outcomes highlight the notion that PTB may be a result of aberrant shifts in maternal microbiota rather than by a single infectious microorganism per se. However, despite several decades documenting the co-association of altered vaginal microbiota and inflammation with spontaneous PTB, neither a clear pathologic agent nor targeted therapy has shown unmitigated success in combatting presumptive infectious or inflammatory PTB.

Lack of clear pathogenic microbes driving spontaneous PTB has spurred interest in the potential role of commensal microbes. Research on the trillions of commensal microorganisms that reside on and within our bodies, collectively known as the human microbiota, has begun to reorient how we think microorganisms may influence pregnancy outcomes. Recent advances in sequencing technologies have enabled in-depth interrogation of these microbial communities and their function without the limitations of culture-based methods.9 The normal vaginal microbiota of healthy non-pregnant and pregnant women has since been comprehensively characterized, providing a reference for the typical microbiota associated with obstetrical health.9–12 Furthermore, the low biomass microbial community of placentae, their membranes, and amniotic fluid in healthy pregnancies has been similarly identified and characterized by several investigators, which has contributed to the emerging body of evidence that is challenging the notion of a sterile intrauterine environment.13–18 These and other studies have subsequently begun to characterize the placental microbiota in cases of PTB, chorioamnionitis and other adverse pregnancy outcomes.18–20 In this review, we will briefly review the current literature exploring associations between the vaginal and placental microbiota and PTB, highlight the remaining gaps in our knowledge, and speculate on how this information may impact future clinical practice.

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